Challenge Topic: 04-HL-108;Improving clinical outcomes in critically ill patients with respiratory failure. Over the past two decades a great deal has been learned about the basic physiology of the breathing muscles and a number of pathophysiological conditions, including sepsis, have been shown to rapidly produce severe respiratory muscle dysfunction in animal models of disease. Importantly, these basic science studies have identified a number of pharmacological agents that appear capable of largely preventing or reversing the development of respiratory muscle dysfunction in animal models of disease. Unfortunately, virtually none of these discoveries have been translated into clinical usage. In fact, it is not even clear which hospitalized patients have respiratory muscle dysfunction, how severe their dysfunction is, and when this dysfunction develops during hospitalization. Based on our own observations, however, we believe severe respiratory muscle weakness develops in a large percentage of critically ill patients. If so, administration of drugs designed to prevent the development of skeletal muscle weakness in this patient population should have a major impact on patient outcomes, reducing the need for respiratory support, shortening the duration of ICU and hospital stay, and ultimately, improving mortality. The purpose of the present proposal is to investigate these issues in detail, to test our central hypothesis that respiratory muscle contractile dysfunction is a major contributor to respiratory failure in critically ill patients, and to translate drug treatments for respiratory muscle dysfunction from the basic science laboratory to the intensive care unit. Aim 1 will systematically evaluate respiratory muscle strength in a large cohort of MICU patients using a state-of-the-art nonvolitional measure of diaphragmatic function, namely assessment of the transdiaphragmatic twitch pressure elicited during bilateral phrenic nerve magnetic stimulation (twitch Pdi). Aim 2 will test the hypothesis that the development of skeletal muscle weakness in critically ill MICU patients can be attenuated by administration of two pharmacological agents (N-acetylcysteine and eicosopentanoic acid). We will compare skeletal muscle force and other outcome measures (duration of mechanical ventilation, duration of ICU and hospital stay) in patients at risk for respiratory muscle weakness randomized to receive either placebo, N- acetylcysteine (NAC), eicosopentanoic acid (EPA), or a combination of NAC and EPA. These experiments will provide the first comprehensive, objective evaluation of the incidence, severity, and evolution of respiratory and limb skeletal muscle dysfunction in critically ill patients. In addition, we will determine if it is possible to prevent the development of skeletal muscle weakness in critically ill patients via administration of two drugs (N-acetylcysteine and eicosopentanoic acid) previously shown in basic science studies to prevent respiratory muscle weakness in animal models of critical illness.